The present invention relates to a production method of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, which is a useful synthetic intermediate of an anti-HIV agent, and an intermediate thereof.
PNU-140690 represented by the following formula (I) 
is known to be useful as an anti-HIV agent being developed in recent years. As a useful synthetic intermediate for PNU-140690, 3-hydroxy-3-(2-phenylethyl)hexanoic acid represented by the following formula (II) 
is known. This 3-hydroxy-3-(2-phenylethyl)hexanoic acid has one asymmetric carbon atom and includes an (R) isomer and an (S) isomer, and only a racemate (racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid) is synthesized according to a conventional method. Of these, an (R) isomer of the following formula (III) 
[(R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid] is preferably used as the above-mentioned synthetic intermediate.
As a method of optical resolution of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid from the above-mentioned racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, a method using (xe2x88x92)-norephedrine [(1S,2S)-norephedrine] has been conventionally reported (J. Org. Chem., Vol. 63, No. 21, 1998, 7348-7356). According to this method, however, (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid having an optical purity of not less than 98% e.e. is obtained after two times of recrystallization of a salt with (xe2x88x92)-norephedrine (92% e.e.), which is industrially inefficient. In addition, a method such as this has a problem that the yield of a highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid throughout the reaction system, in other words, the total yield of highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid relative to racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid (hereinafter sometimes to be simply referred to as xe2x80x9ctotal yieldxe2x80x9d) is low (about 27%). In the above-mentioned report, it is described that even the use of generally used amine, such as phenylglycinol, ephedrine, sparteine and xcex1-methylbenzylamine, did not lead to an effective optical resolution, and there is a demand on a method capable of efficiently affording highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid in a higher total yield.
In the meantime, as an intermediate for the above-mentioned 3-hydroxy-3-(2-phenylethyl)hexanoic acid, racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate of the following formula (IV) 
is known.
As a method for producing such racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate, a method comprising addition of a lithium salt of ethyl acetate to 1-phenyl-3-hexanone in tetrahydrofuran (THF) is known. For preparation of a lithium salt of ethyl acetate, however, deprotonation from ethyl acetate with a strong base such as lithium dialkylamide and the like is necessary, which is generally conducted by a reaction at an ultra-low temperature at around xe2x88x9278xc2x0 C. (WO99/12919, Kristina S Fors et al, J. Org. Chem. 1998, 63, 7348-7356). A reaction at such an ultra-low temperature contains many industrially disadvantageous aspects, for example, it requires a special cooling unit and the operation is complicated and the like.
As a method for producing racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate in a temperature range that does not require a special cooling unit, the use of Reformatskii reaction is considered. The Reformatskii reaction is a conventionally known reaction which produces xcex2-hydroxyacid ester by condensation of xcex1-halogen ester and a carbonyl compound such as aldehyde, ketone and the like in the presence of zinc. For this Reformatskii reaction to proceed smoothly, the above-mentioned zinc needs to have a high activity (reactivity). As a method for producing activated zinc, the following conventional methods (1)-(5) are known. Any activated zinc obtained by these methods has a problem as shown in the following. The method is not practical for use for the above-mentioned Reformatskii reaction and racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate could not be obtained in a sufficient yield.
(1) A Method for Preparing Metallic Zinc by Reducing Zinc Salt Such as Zinc Chloride and the Like with Potassium, Magnesium, Lithium and the Like.
This method has a problem in safety because a water-prohibiting metal is used and the like.
(2) A Method for Activating Metallic Zinc with Hydrochloric Acid.
According to this method, application to a Reformatskii reaction, which is a water-prohibiting reaction, requires activation of zinc, complete removal of the acid and drying, and the preparation is complicated and impractical.
(3) A Method for Activating Zinc by treating Metallic Zinc with a Copper Salt or Silver Salt in Acetic Acid to Give an Alloy with Copper or Silver.
Because alloy is prepared in acetic acid, acetic acid needs to be completely removed by washing with water, and only after drying on washing with water, can it be used for a Reformatskii reaction, which is a water-prohibiting reaction, and the preparation is complicated and impractical.
(4) A Method for Activating Zinc by Ultrasonic Wave.
In this method, every facility used for the production of activated zinc requires a sufficiently strong ultrasonic oscillator. Therefore, this method is not entirely practical.
(5) A Method for Activating Zinc by Stirring Zinc with Chlorotrimethylsilane in Ether.
This method is defective in that a highly inflammable solvent such as ether is used and the activity of the obtained zinc is not always high enough.
In the reaction using the above-mentioned activated zinc, a waste containing zinc is produced and a special waste treatment is necessary to avoid environmental pollution.
In the above-mentioned reaction, a bromoacetic acid ester is used. Bromoacetic acid ester is expensive and shows strong tearing property, and the reaction using the same has safety and health problems.
The present invention has been made to solve the above-mentioned problems and aims at providing a production method capable of efficient production of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid useful as a starting material of a pharmaceutical agent from racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, with a high optical purity and in a relatively high total yield.
In addition, another object of the present invention is to provide a method of producing 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester safely and at a lower cost than a conventional method, by the use of general production apparatuses.
As a result of intensive studies in an attempt to solve the above-mentioned problems, the present inventors have completed the present invention. The present invention provides the following.
[1] A production method of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, which comprises optically resolving racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid using an optically active amine of the formula (VIII) 
wherein R2 is 3,4-dimethoxyphenyl or 2-chlorophenyl (hereinafter to be also referred to as xe2x80x9coptically active amine (VIII)xe2x80x9d).
[2] The production method of the above-mentioned [1], wherein a salt of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid with the optically active amine (VIII) is crystallized in one or more kinds of solvents selected from ethyl acetate, methanol, isopropanol, ethanol, acetonitrile, methyl isobutyl ketone (MIBK), acetone, methyl ethyl ketone, diisopropyl ether, dimethoxyethane and THF, wherein the solvent optionally further contains water.
[3] The production method of the above-mentioned [1], wherein the optically active amine (VIII) is obtained by condensing (R)-1-phenylethylamine with a compound of the formula R2xe2x80x94CHO (VIII-i) wherein R2 is as defined above, and reducing the resulting compound.
[4] The production method of the above-mentioned [1], which comprises recovering the optically active amine (VIII) after optical resolution.
[5] A production method of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, which comprises hydrolyzing a racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester to produce racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, extracting the compound with one or more kinds of solvents selected from ethyl acetate, MIBK, methyl ethyl ketone, diisopropyl ether and THF, and optically resolving the compound by crystallizing a salt of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid with an optically active amine (VIII) using a part or the entirety left of the extraction solvent as a solvent for optical resolution.
[6] The production method of the above-mentioned [5], wherein the optically active amine (VIII) is produced by condensing (R)-1-phenylethylamine with a compound of the formula R2xe2x80x94CHO (VIII-i) wherein R2 is as defined above, and reducing the resulting compound.
[7] The production method of the above-mentioned [5], which comprises recovering the optically active amine (VIII) after optical resolution.
[8] A production method of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, which comprises reacting magnesium, a haloacetic acid ester and 1-phenyl-3-hexanone to produce racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester, hydrolyzing this compound to give racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, and optically resolving this compound using the optically active amine (VIII).
[9] The production method of the above-mentioned [8], wherein the haloacetic acid ester is a chloroacetic acid ester.
[10] The production method of the above-mentioned [8], wherein a salt of the (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid with the optically active amine (VIII) is crystallized in one or more kinds of solvents selected from ethyl acetate, methanol, isopropanol, ethanol, acetonitrile, MIBK, acetone, methyl ethyl ketone, diisopropyl ether, dimethoxyethane and THF, wherein the solvent optionally further contains water.
[11] The production method of the above-mentioned [8], wherein, after producing the racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, the resulting compound is extracted with one or more kinds of solvents selected from ethyl acetate, MIBK, methyl ethyl ketone, diisopropyl ether and THF, and optically resolved by crystallizing the salt of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid with an optically active amine (VIII) using a part or the entirety left of the extraction solvent as a solvent for optical resolution.
[12] The production method of the above-mentioned [8], wherein the optically active amine (VIII) is obtained by condensing (R)-1-phenylethylamine with a compound of the formula R2xe2x80x94CHO (VIII-i) wherein R2 is as defined above, and reducing the resulting compound.
[13] The production method of the above-mentioned [8], which comprises recovering the optically active amine (VIII) after optical resolution.
[14] The production method of the above-mentioned [8], wherein magnesium is activated.
[15] The production method of the above-mentioned [14], wherein magnesium is activated with chlorosilanes and halogenated hydrocarbon.
[16] The production method of the above-mentioned [15], wherein the chlorosilanes is selected from the group consisting of chlorotrimethylsilane, dichlorodimethylsilane, methyltrichlorosilane and tetrachlorosilane.
[17] The production method of the above-mentioned [15], wherein the halogenated hydrocarbon is selected from the group consisting of allyl bromide, iodomethane, iodoethane, benzyl bromide, 1,2-diiodoethane and 1,2-dibromoethane.
[18] The production method of the above-mentioned [8], wherein 1-phenyl-3-hexanone is obtained by condensing benzaldehyde with 2-pentanone in the presence of a base to give propyl styryl ketone, and reducing the obtained propyl styryl ketone.
[19] A production method of a racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester, which comprises reacting magnesium, haloacetic acid ester and 1-phenyl-3-hexanone.
[20] The production method of the above-mentioned [19], wherein the haloacetic acid ester is a chloroacetic acid ester.
[21] The production method of the above-mentioned [19], wherein magnesium is activated.
[22] The production method of the above-mentioned [21], wherein magnesium is activated with chlorosilanes and halogenated hydrocarbon.
[23] The production method of the above-mentioned [22], wherein chlorosilanes is selected from the group consisting of chlorotrimethylsilane, dichlorodimethylsilane, methyltrichlorosilane and tetrachlorosilane.
[24] The production method of the above-mentioned [22], wherein halogenated hydrocarbon is selected from the group consisting of allyl bromide, iodomethane, iodoethane, benzyl bromide, 1,2-diiodoethane and 1,2-dibromoethane.
[25] The production method of the above-mentioned [19], wherein 1-phenyl-3-hexanone is obtained by condensing benzaldehyde with 2-pentanone in the presence of a base to give propyl styryl ketone, and reducing the obtained propyl styryl ketone.
In the present specification, the term xe2x80x9cracemicxe2x80x9d is used to show that the compound preceded by this term is a mixture of enantiomers ((R)-isomer and (S)-isomer) that can be optically resolved, and is not to be construed as limiting the compound only to a mixture of equivalent amounts of (R)-isomer and (S)-isomer.
The production method of the present invention comprises, as shown in the following reaction scheme 1, a part or the entirety of the steps of
(a): a step for producing a racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester of the formula (VII) (hereinafter to be also referred to as xe2x80x9cracemic carboxylic acid ester (VII)xe2x80x9d) by reacting 1-phenyl-3-hexanone of the formula (V) (hereinafter to be also referred to as xe2x80x9cketone (V)xe2x80x9d), a haloacetic acid ester of the formula (VI) (hereinafter to be also referred to as xe2x80x9cester (VI)xe2x80x9d) and magnesium,
(b): a step for producing racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid of the formula (II) (hereinafter to be also referred to as xe2x80x9cracemic carboxylic acid (II)xe2x80x9d) by hydrolyzing the racemic carboxylic acid ester (VII), and
(c): a step for producing (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid of the formula (III) (hereinafter to be also referred to as xe2x80x9c(R)-carboxylic acid (III)xe2x80x9d) by optical resolution of racemic carboxylic acid (II) using the optically active amine (VIII). 
wherein R1 is free of particular limitation as long as it does not influence the reaction, X is a halogen atom and R2 is 3,4-dimethoxyphenyl or 2-chlorophenyl.
Each step is explained in the following.
1. Production Step of Racemic 3-hydroxy-3-(2-phenylethyl)hexanoic Acid Ester [Step (a)]
This step (a) comprises, as shown in the above-mentioned scheme 1, reacting 1-phenyl-3-hexanone [ketone (V)], haloacetic acid ester [ester (VI)] and magnesium to give racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester [racemic carboxylic acid ester (VII)].
This reaction is realized by, for example, simultaneously adding ketone (V) and ester (VI) to magnesium charged in the solvent in advance, or adding ester (VI) to a mixture of ketone (V) and magnesium charged in the solvent in advance.
In the above-mentioned reaction, the amount of magnesium to be used is preferably 1 mole-5 moles, per 1 mole of ketone (V), but from an economic aspect, it is more preferably 1.1 moles-2.0 moles. In the above-mentioned reaction, when the amount of magnesium to be used is less than 1 mole per 1 mole of ketone (V), ketone (V) partly may remain unreacted, thereby possibly lowering the reaction efficiency. In the above-mentioned reaction, moreover, the use of magnesium in a proportion of more than 5 moles per 1 mole of ketone (V) is economically useless, because the amount of magnesium unrelated to the reaction becomes large.
In the above-mentioned reaction, the amount of ester (VI) to be used is preferably 1 mole-3 moles per 1 mole of ketone (V), but from the economic aspect, it is more preferably 1 mole-2 moles. In the above-mentioned reaction, when the amount of ester (VI) to be used is less than 1 mole per 1 mole of ketone (V), ketone (V) partly may remain unreacted, thereby possibly lowering the reaction efficiency. In the above-mentioned reaction, moreover, when the amount of ester (VI) to be used exceeds 3 moles per 1 mole of ketone (V), it is economically useless, because the amount of ester (VI) unrelated to the reaction becomes large, and moreover, the ester remained in the resulting product may make purification of the product difficult.
The ester (VI) to be used for the above-mentioned step (a) is free of any particular limitation as long as X is a halogen atom and R1 does not influence the reaction. X in the formula (VI) is exemplified by chlorine atom, bromine atom, iodine atom and the like, with preference given to chlorine atom. As R1 in the formula (VI), straight or branched chain alkyl group having 1-6 carbon atoms (e.g., methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.) is exemplified, with preference given to straight or branched chain alkyl group having 1-4 carbon atoms (e.g., methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).
As preferable ester (VI), a chloroacetic acid ester, wherein X of the formula (VI) is chlorine atom, is mentioned, more preferably a chloroacetic acid alkyl ester, wherein X is chlorine atom and R1 is straight or branched chain alkyl group having 1-6, preferably 1-4, carbon atoms. Specific examples thereof include methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, n-butyl chloroacetate, tert-butyl chloroacetate and the like. Of these, use of ethyl chloroacetate or tert-butyl chloroacetate is preferable, because it is easily obtained.
The above-mentioned reaction is generally carried out in a temperature range of 15xc2x0 C.-100xc2x0 C., preferably 20xc2x0 C.-70xc2x0 C. When the reaction temperature is lower than 15xc2x0 C., the reaction may proceed slowly or may not proceed at all. When the reaction temperature exceeds 100xc2x0 C., the starting material, ketone (V), may be decomposed in the reaction mixture, or the resulting product, racemic carboxylic acid ester (VII) may be decomposed, thus lowering the yield of the reaction.
The above-mentioned reaction is generally carried out in 30 min-20 hr by the addition of ester (VI) to a mixture of ketone (V) and magnesium, or by the simultaneous addition of ketone (V) and ester (VI) to magnesium.
The solvent to be used for the above-mentioned reaction may be any as long as it does not inhibit the reaction, and ethers such as THF, dioxane, dimethoxyethane and the like and a mixed solvent of the ethers and any solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene and the like, aliphatic hydrocarbons such as heptane, hexane, octane and the like can be preferably used. When a mixed solvent is to be used, a typical conventionally-known mixing ratio may be applied for mixing.
The amount of the solvent to be used is generally 100 mL-2000 mL, preferably 150 mL-1500 mL, per 1 mole of ketone (V) for smooth reaction and improved productivity by reaction.
By the above-mentioned step (a), racemic carboxylic acid ester (VII) can be produced safely at a lower cost than by a conventional manner.
That is, because the above-mentioned step (a) differs from a conventional method that uses lithium dialkylamide, and does not require a reaction at around an ultra-low temperature (around xe2x88x9278xc2x0 C.), production can be done efficiently without a need for a special cooling unit. In addition, because expensive lithium dialkylamide is not used, racemic carboxylic acid ester (VII) can be produced at a lower cost. According to the above-mentioned step (a), moreover, a highly inflammable solvent is not used, unlike methods using activated zinc and ethyl bromoacetate, and therefore, the method is safe and can conveniently produce racemic carboxylic acid ester (VII) without a waste treatment. The activation of magnesium is easy as compared to the aforementioned preparation of activated zinc, and the operation of the production is efficient. In the above-mentioned step (a), moreover, haloacetic acid ester (e.g., chloroacetic acid ester) other than expensive and highly tearing bromoacetic acid ester can be used, in which case racemic carboxylic acid ester (VII) can be produced at a low cost without any safety or hygienic problem.
In the above-mentioned step (a), magnesium to be used is preferably activated. In the above-mentioned step (a), magnesium, whether activated or not, affords the above-mentioned effect, but the use of activated magnesium makes the reaction to produce racemic carboxylic acid ester (VII) smooth and safer.
As used herein, by the xe2x80x9cactivation of magnesiumxe2x80x9d is meant removal of a substance inhibiting reaction on magnesium surface (in many cases it is a film of magnesium oxide) to enhance the reactivity. As a method for activating magnesium, for example, (1) activation by a combination of chlorotrimethylsilane and zinc chloride, (2) activation by chlorotrimethylsilane alone, (3) activation by iodine alone, (4) activation by a combination of iodine and ethyl bromoacetate, (5) activation by a combination of chlorosilanes and halogenated hydrocarbon, and the like are mentioned (hereinafter xe2x80x9cchlorotrimethylsilane and zinc chloridexe2x80x9d to be used for the method of the above-mentioned (1), xe2x80x9cchlorotrimethylsilanexe2x80x9d to be used for the method of the above-mentioned (2), xe2x80x9ciodinexe2x80x9d to be used for the method of the above-mentioned (3), xe2x80x9ciodine and ethyl bromoacetatexe2x80x9d to be used for the method of the above-mentioned (4) and xe2x80x9cchlorosilanes and halogenated hydrocarbonxe2x80x9d to be used for the method of the above-mentioned (5) are also collectively referred to as xe2x80x9cactivatorxe2x80x9d). Of these, the activation method by chlorotrimethylsilane alone of the above-mentioned (2) is more preferable, because activation is easy and a starting material difficult to handle is not used. In addition, the activation method by chlorosilanes and halogenated hydrocarbon of the above-mentioned (5) is more preferable, because magnesium can be more effectively activated than iodine, iodomethane, chlorotrimethylsilane and the like used alone.
For the activation of magnesium in the above-mentioned step (a), an activator only needs to be added immediately before or simultaneously with the start of the reaction of magnesium, ketone (V) and ester (VI) in a solvent in the above-mentioned reaction.
To be specific, an activator is added to magnesium charged in the solvent in advance, or a mixture of ketone (V), ester (VI) and an activator is added, or a mixture of ketone (V) and ester (VI) and an activator may be added separately, to magnesium charged in the solvent in advance. Alternatively, a mixture of ester (VI) and an activator is added, or ester (VI) and an activator may be added separately, to a mixture of ketone (V) and magnesium charged in the solvent in advance. When the above-mentioned activator is separately added, it is preferably added immediately before addition of a mixture of ketone (V) and ester (VI) or ester (VI), or simultaneously added (more preferably simultaneously added in a thin stream). For addition of the above-mentioned activator, a part of ketone (V) and ester (VI) is added in advance and an activator is added and stirred for a suitable period of time (or stirring and suitable temperature rise), after which the remaining ketone (V) and ester (VI) may be added. When the activator is to be added separately, the activator may be prepared into a solution containing the activator in advance depending on the kind thereof. In this case, the solvent therefor is preferably the aforementioned solvent used for the reaction.
Each method for activating magnesium in the above-mentioned step (a) is specifically explained in the following.
(1) Activation by Chlorotrimethylsilane and Zinc Chloride in Combination
When magnesium is activated by combining chlorotrimethylsilane and zinc chloride, the amount of chlorotrimethylsilane to be used is preferably 0.005 mole-0.05 mole, more preferably 0.01 mole-0.05 mole, per 1 mole of magnesium. When the amount of chlorotrimethylsilane to be used is less than 0.005 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of chlorotrimethylsilane to be used exceeds 0.05 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with chlorotrimethylsilane, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
The amount of zinc chloride to be used is preferably 0.01 mole-0.1 mole, more preferably 0.01 mole-0.07 mole, per 1 mole of magnesium. When the amount of zinc chloride to be used is less than 0.01 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of zinc chloride to be used exceeds 0.1 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with zinc chloride, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
In a method for producing racemic carboxylic acid ester (VII) in the above-mentioned step (a), when magnesium is activated by combining chlorotrimethylsilane and zinc chloride, the temperature of the above-mentioned reaction conditions is particularly preferably in the range of 25xc2x0 C.-70xc2x0 C. from the aforementioned range, and the time is particularly preferably 2 hr-10 hr from the aforementioned range.
When magnesium is activated by combining chlorotrimethylsilane and zinc chloride as mentioned above, activation is performed particularly effectively as compared to activation of magnesium by a different method. This is beneficial because the objective reaction can be started at a lower temperature.
(2) Activation by Chlorotrimethylsilane Alone
In the above-mentioned step (a), magnesium may be activated using chlorotrimethylsilane alone. The amount of chlorotrimethylsilane to be used is preferably 0.005 mole-0.2 mole, more preferably 0.01 mole-0.1 mole, per 1 mole of magnesium. When the amount of chlorotrimethylsilane to be used is less than 0.005 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of chlorotrimethylsilane to be used exceeds 0.1 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with chlorotrimethylsilane, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
In a method for producing racemic carboxylic acid ester (VII) in the above-mentioned step (a), when magnesium is activated by chlorotrimethylsilane alone, the temperature of the above-mentioned reaction conditions is particularly preferably in the range of 20xc2x0 C.-60xc2x0 C. from the aforementioned range, and the time is particularly preferably 2 hr-10 hr from the aforementioned range.
When magnesium is activated by using chlorotrimethylsilane alone as mentioned above, activation of magnesium is performed particularly effectively as compared to activation of magnesium by a different method. This is beneficial because the objective reaction can be started at a lower temperature and elements problematic to the environment do not need to be used.
(3) Activation by Iodine Alone
In the above-mentioned step (a), magnesium may be activated using iodine alone as an activator. The amount of iodine to be used is preferably 0.0001 mole-0.01 mole and more preferably 0.0003 mole-0.002 mole, per 1 mole of magnesium. When the amount of iodine to be used is less than 0.0001 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of iodine to be used exceeds 0.01 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with iodine, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
In a method for producing racemic carboxylic acid ester (VII) in the above-mentioned step (a), when magnesium is activated by iodine alone, the temperature of the above-mentioned reaction conditions is particularly preferably in the range of 25xc2x0 C.-65xc2x0 C. from the aforementioned range, and the time is particularly preferably 2 hr-10 hr from the aforementioned range.
By using iodine alone for activation of magnesium as mentioned above, particularly the brown color of the reaction solution disappears when magnesium is activated, when compared to the case where magnesium is activated by other method, which advantageously facilitates confirmation of activation.
(4) Activation by Iodine and Ethyl Bromoacetate in Combination
In the above-mentioned step (a), ethyl bromoacetate may be used in addition to the above-mentioned iodine to activate magnesium. When magnesium is activated by combining iodine and ethyl bromoacetate, the amount of iodine to be used is preferably 0.0001 mole-0.01 mole, more preferably 0.0003 mole-0.002 mole, per 1 mole of magnesium for the same reason as given for the above-mentioned (3).
The amount of ethyl bromoacetate to be used is preferably 0.001 mole-0.01 mole, more preferably 0.002 mole-0.005 mole, per 1 mole of magnesium. When the amount of ethyl bromoacetate to be used is less than 0.001 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of ethyl bromoacetate to be used exceeds 0.01 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with ethyl bromoacetate, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
In a method for producing racemic carboxylic acid ester (VII) in the above-mentioned step (a), when magnesium is activated by combining iodine and ethyl bromoacetate, the temperature of the above-mentioned reaction conditions is particularly preferably in the range of 35xc2x0 C.-70xc2x0 C. from the aforementioned range, and the time is particularly preferably 2 hr-10 hr from the aforementioned range. In this case, iodine may be added first and then ethyl bromoacetate may be added.
By using iodine and ethyl bromoacetate in combination for activation of magnesium as mentioned above, particularly the reaction mixture turn to bear a green color along with the activation of magnesium, when compared to the case where magnesium is activated by other method, which advantageously facilitates confirmation of activation.
(5) Activation by Chlorosilanes and Halogenated Hydrocarbon in Combination
A method for producing racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester by activation of magnesium by a combination of the chlorosilanes and halogenated hydrocarbon is applicable to the production of other 3-hydroxycarboxylic acid esters. This method is explained in the following including the production of other 3-hydroxycarboxylic acid esters.
This method is, as shown in the following scheme, a production method comprising reacting a carbonyl compound of the formula (i) (hereinafter to be also referred to as xe2x80x9ccarbonyl compound (i)xe2x80x9d), the above-mentioned ester (VI) and magnesium activated by chlorosilanes and halogenated hydrocarbon to give 3-hydroxycarboxylic acid ester (ii) of the formula (ii) (hereinafter to be also referred to as xe2x80x9cester (ii)xe2x80x9d), such as the above-mentioned racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester [racemic carboxylic acid ester (VII)]. 
wherein R1a and R2a are free of particular limitation as long as they do not show an influence on the reaction, and R1 and X are as defined above.
The carbonyl compound (i) to be used for this production method is not subject to any particular limitation as long as it is aldehyde or ketone that can react with ester (VI) to give ester (ii). For example, aldehyde or ketone of the formula (i), wherein R1a is a lower alkyl group optionally having substituents, an aryl group optionally having substituents, an aralkyl group optionally having substituents and the like, and R2a is hydrogen atom, a lower alkyl group optionally having substituents, an aryl group optionally having substituents, an aralkyl group optionally having substituents can be mentioned. Specific examples include acetaldehyde, benzaldehyde, acetone, methyl ethyl ketone, acetophenone, benzophenone, 1-phenyl-3-hexanone [the above-mentioned ketone (V)] and the like, with preference given to 1-phenyl-3-hexanone [the above-mentioned ketone (V)] because it is a synthetic intermediate for PNU-140690 useful as an anti-HIV agent.
As the xe2x80x9clower alkyl groupxe2x80x9d of the xe2x80x9clower alkyl group optionally having substituentsxe2x80x9d for the above-mentioned R1a and R2a, a straight or branched chain alkyl group having 1-10, preferably 2-7, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, with preference given to propyl, isopropyl, butyl, pentyl, hexyl, heptyl and the like.
The xe2x80x9caryl groupxe2x80x9d of the xe2x80x9caryl group optionally having substituentsxe2x80x9d for the above-mentioned R1a and R2a is exemplified by phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and the like, with preference given to phenyl, 1-naphthyl, 2-naphthyl and the like.
The xe2x80x9caralkyl groupxe2x80x9d of the xe2x80x9caralkyl group optionally having substituentsxe2x80x9d for the above-mentioned R1a and R2a is exemplified by an aralkyl group wherein the aryl moiety is the same as the above-mentioned xe2x80x9caryl groupxe2x80x9d and the alkyl moiety has 1-10, preferably 2-5, carbon atoms. Examples thereof include benzyl, 1-phenethyl, 2-phenethyl, 3-phenylpropyl and the like, with preference given to 2-phenethyl and the like.
The xe2x80x9csubstituentxe2x80x9d of the xe2x80x9clower alkyl group optionally having substituentsxe2x80x9d, xe2x80x9caryl group optionally having substituentsxe2x80x9d and xe2x80x9caralkyl group optionally having substituentsxe2x80x9d for the above-mentioned R1a and R2a is not subject to any particular limitation as long as it does not inhibit the reaction, and is exemplified by lower alkyl group (such as those mentioned above, that cannot be a substituent for the xe2x80x9clower alkyl group optionally having substituentsxe2x80x9d), halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), lower alkoxy group, aryloxy group, aralkyloxy group, dialkylamino group and the like. The number of the substituent is not particularly limited and is preferably 1-3, wherein the substituents may be the same or different.
As the xe2x80x9clower alkoxy groupxe2x80x9d for the above-mentioned substituent, a linear or branched chain alkoxy group having carbon atoms 1-10 can be mentioned, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
As the xe2x80x9caryloxy groupxe2x80x9dfor the above-mentioned substituent, phenoxy, 1-naphthoxy, 2-naphthoxy, 1-anthryloxy, 2-anthryloxy, 9-anthryloxy and the like can be mentioned.
As the xe2x80x9caralkyloxy groupxe2x80x9d for the above-mentioned substituent, benzyloxy, 1-phenethyloxy, 2-phenethyloxy, 3-phenylpropoxy and the like can be mentioned.
As the xe2x80x9cdialkylamino groupxe2x80x9d for the above-mentioned substituent, a dialkylamino group having linear or branched chain alkyl moiety having 1-6 carbon atoms can be mentioned, wherein the alkyl moieties are the same or different. Examples thereof include dimethylamino, diethylamino, ethylmethylamino and the like.
The xe2x80x9cchlorosilanesxe2x80x9d to be used for the above-mentioned method are not subject to any particular limitation as long as they can activate magnesium. Examples thereof include chlorosilanes of the formula (iii)
R3anSiCl(4-n)xe2x80x83xe2x80x83(iii)
wherein R3a is a lower alkyl group or aryl group and n is an integer of 0-3. As the xe2x80x9clower alkyl groupxe2x80x9d and xe2x80x9caryl groupxe2x80x9d for R3a, those exemplified for the xe2x80x9clower alkyl groupsxe2x80x9d and xe2x80x9caryl groupxe2x80x9d of the above-mentioned R1a and R2a can be mentioned.
Chlorosilanes are concretely exemplified by chlorotrimethylsilane, dichlorodimethylsilane, methyltrichlorosilane, tetrachlorosilane and the like.
The xe2x80x9chalogenated hydrocarbonxe2x80x9d to be used for the above-mentioned method is not subject to any particular limitation as long as it can activate magnesium. Examples thereof include hydrocarbon wherein 1 or 2 optional hydrogen atoms are substituted by halogen atom. By the xe2x80x9chalogen atomxe2x80x9d is meant chlorine atom, bromine atom, iodine atom and the like, and by the xe2x80x9chydrocarbonxe2x80x9d is meant straight or branched chain alkane, alkene, alkyne and the like, having 1-10, preferably 1-7, carbon atoms and optionally having substituents. Examples of the substituent include aryl group (e.g., phenyl group, 1-naphthyl, 2-naphthyl, etc.) and the like.
As the halogenated hydrocarbon, allyl bromide, iodomethane, iodoethane, benzyl bromide, 1,2-diiodoethane, 1,2-dibromoethane and the like are specifically mentioned, with preference given to allyl bromide, iodomethane and 1,2-dibromoethane.
The above-mentioned method is realized by simultaneous addition of carbonyl compound (i) and ester (VI) to magnesium charged in a solvent in advance, or by the addition of ester (VI) to a mixture of carbonyl compound (i) and magnesium charged in a solvent in advance.
In the above-mentioned method, chlorosilanes and halogenated hydrocarbon are added to activate magnesium. As used herein, by the xe2x80x9cactivate magnesiumxe2x80x9d is meant removing a substance on magnesium surface that inhibits reaction (in many cases, it is a film of oxidized magnesium) to enhance reactivity.
The activation of magnesium by chlorosilanes and halogenated hydrocarbon may be conducted immediately before the start of the reaction or along with the progress of the reaction or both. To be specific, chlorosilanes and halogenated hydrocarbon are added to magnesium charged in a solvent in advance; a mixture of carbonyl compound (i), ester (VI), chlorosilanes and halogenated hydrocarbon is added to magnesium charged in a solvent in advance; a mixture of carbonyl compound (i) and ester (VI), and a mixture of chlorosilanes and halogenated hydrocarbon are separately added to magnesium charged in a solvent in advance; halogenated hydrocarbon is added to magnesium charged in a solvent in advance, and then a mixture of carbonyl compound (i), ester (VI) and chlorosilanes is added; halogenated hydrocarbon is added to magnesium charged in a solvent in advance, and then a mixture of carbonyl compound (i) and ester (VI), and chlorosilanes are separately added; halogenated hydrocarbon is added to magnesium charged in a solvent in advance, and then a mixture of carbonyl compound (i), ester (VI), chlorosilanes and halogenated hydrocarbon is added; halogenated hydrocarbon is added to magnesium charged in a solvent in advance, and then a mixture of carbonyl compound (i) and ester (VI), and a mixture of chlorosilanes and halogenated hydrocarbon are separately added; a mixture of ester (VI), chlorosilanes and halogenated hydrocarbon is added to a mixture of carbonyl compound (i) and magnesium charged in a solvent in advance; ester (VI), and a mixture of chlorosilanes and halogenated hydrocarbon is separately added to a mixture of carbonyl compound (i) and magnesium charged in a solvent in advance; halogenated hydrocarbon is added to a mixture of carbonyl compound (i) and magnesium charged in a solvent in advance, and then a mixture of ester (VI), chlorosilanes and halogenated hydrocarbon is added; halogenated hydrocarbon is added to a mixture of carbonyl compound (i) and magnesium charged in a solvent in advance, and then ester (VI) and a mixture of chlorosilanes and halogenated hydrocarbon is added separately and the like, but the activation is not limited to these. When chlorosilanes or halogenated hydrocarbon is added separately, they are preferably added immediately before addition of a mixture of carbonyl compound (i) and ester (VI) or ester (VI), or simultaneously therewith (more preferably simultaneously added in a thin stream). For the addition of the above-mentioned chlorosilanes or halogenated hydrocarbon, a part of carbonyl compound (i) and ester (VI) are added, chlorosilane or halogenated hydrocarbon is added and stirred for a suitable time (or stirring and suitable temperature rise), and then the remaining carbonyl compound (i) and ester (VI) may be added. When chlorosilane or halogenated hydrocarbon is added separately, it may be prepared in advance into a solvent containing the same.
In the above-mentioned reaction, the amount of magnesium to be used is preferably 0.5 mole-5 moles per 1 mole of carbonyl compound (i), but it is more preferably 0.9 mole-2 moles from the economic aspect. In the above-mentioned reaction, when the amount of magnesium to be used is less than 0.5 mole per 1 mole of carbonyl compound (i), the efficiency of the reaction may be unpreferably degraded markedly due to the carbonyl compound (i) remaining partially unreacted. In the above-mentioned reaction, moreover, the use of magnesium in excess of 5 moles per 1 mole of carbonyl compound (i) is economically useless, because it leads to the use of a large amount of magnesium not involved in the reaction.
In the above-mentioned reaction, the amount of ester (VI) to be used is preferably 1 mole-3 moles per 1 mole of carbonyl compound (i), more preferably 1 mole-2 moles from the economic aspect. In the above-mentioned reaction, when the amount of ester (VI) to be used is less than 1 mole per 1 mole of carbonyl compound (i), the efficiency of the reaction may be markedly degraded due to the carbonyl compound (i) remaining partially unreacted. In the above-mentioned reaction, moreover, the use of ester (VI) in excess of 3 moles per 1 mole of carbonyl compound (i) is economically useless and makes purification of the product difficult as well, because it leads to the use of a large amount of ester unnecessary for the reaction with carbonyl compound (i).
In the above-mentioned reaction, the amount of chlorosilanes to be used is preferably 0.005 mole-0.2 mole, more preferably 0.01 mole-0.05 mole, per 1 mole of magnesium. When the amount of chlorosilanes to be used is less than 0.005 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of chlorosilanes to be used exceeds 0.2 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with chlorosilanes, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous.
In the above-mentioned reaction, the amount of halogenated hydrocarbon to be used is preferably 0.001 mole-0.2 mole, more preferable 0.005 mole-0.05 mole, per 1 mole of magnesium. When the amount of halogenated hydrocarbon to be used is less than 0.001 mole per 1 mole of magnesium, magnesium may not be sufficiently activated and the objective reaction may not be started smoothly. When the amount of halogenated hydrocarbon to be used exceeds 0.2 mole per 1 mole of magnesium, magnesium may be consumed by the reaction with halogenated hydrocarbon, thereby possibly necessitating an excess amount of magnesium to complete the reaction, which is economically disadvantageous, and the yield may decrease due to a side reaction.
The above-mentioned reaction is carried out in the temperature range of generally 15xc2x0 C.-100xc2x0 C., preferably 20xc2x0 C.-70xc2x0 C. This is because, when the reaction temperature is less than 15xc2x0 C., the reaction may proceed slowly, or the reaction may not proceed at all, and when the reaction temperature exceeds 100xc2x0 C., carbonyl compound (i), which is a starting material, may be decomposed in the reaction mixture, or ester (ii), which is a resulting product, may be decomposed to possibly reduce the reaction yield. The above-mentioned reaction is generally carried out for 30 min-20 hr.
The solvent to be used for the above-mentioned reaction may be any as long as it does not inhibit the reaction, and ethers such as THF, dioxane, dimethoxyethane and the like, or a mixed solvent of such ethers and any selected from aromatic hydrocarbons, such as benzene, toluene, xylene and the like, and aliphatic hydrocarbons such as heptane, hexane, octane and the like, are preferably used. When a mixed solvent is to be used, they may be mixed at a conventionally known optional proportion.
The total amount of the solvent to be used is generally 100 mL-2000 mL per 1 mole of carbonyl compound (i), and for a smooth reaction and enhanced productivity of the reaction, it is preferably 150 mL-1500 mL.
In the above-mentioned method, by using 1-phenyl-3-hexanone [ketone (V)] as carbonyl compound (i) and setting various reaction conditions that are the same conditions as in said method, racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester [racemic carboxylic acid ester (VII)] can be obtained.
The racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester [racemic carboxylic acid ester (VII)] obtained in the above-mentioned step (a) can be isolated and purified by a conventional method. For example, the reaction mixture is poured into acidic water, and after partitioning, the organic layer is washed and filtrated. The obtained filtrate is washed, dried and concentrated under reduced pressure to isolate racemic carboxylic acid ester (VII). After isolation, for example, it may be subjected to silica gel column chromatography for purification. In addition, racemic carboxylic acid ester (VII) may be subjected to step (b) to be mentioned below without purification.
The ester (VI) to be used for the above-mentioned step (a) can be obtained by various conventionally known methods, or a commercially available one may be used.
The ketone (V) to be used for the above-mentioned step (a) can be produced according to a method described in US publication No. 2002/0013501A or a method comprising oxidization of 1-phenyl-3-hexanol with hypochlorite (JP-A-2002-265409), or a commercially available one can be used. However, one obtained by the following method proposed by the present inventors is preferable.
Production Method of 1-phenyl-3-hexanone (V)
1-Phenyl-3-hexanone [ketone (V)] can be obtained by condensing benzaldehyde of the formula (V-i) with 2-pentanone of the formula (V-ii) in the presence of a base as shown in the following reaction scheme to give propyl styryl ketone of the formula (V-iii), and then reducing the obtained propyl styryl ketone (V-iii). 
Each step is explained in the following.
Step V-1
This step is for obtaining propyl styryl ketone (V-iii) by condensing benzaldehyde (V-i) with 2-pentanone (V-ii).
In this condensation reaction, 2-pentanone (V-ii) is preferably used generally in a proportion of 1.1 mol-5.0 mol, but preferably in a proportion of 2.0 mol-3.5 mol, relative to 1 mol of benzaldehyde (V-i) in view of the reaction time.
The solvent to be used for this reaction is not subject to any particular limitation as long as it does not inhibit the reaction. Generally, a solvent such as water, primary or secondary alcohols (e.g., methanol, ethanol, isopropanol, etc.), tertiary alcohols (e.g., tert-butanol, tert-amyl alcohol, etc.), aromatic compound (e.g., toluene, monochlorobenzene, etc.), ethers (e.g., THF, dioxane, etc.), 2-pentanone, which is a starting material, and the like or a mixed solvents thereof are used. This solvent is preferably used in an amount of generally 50 mL-500 mL relative to 1 mole of benzaldehyde (V-i). From the economic aspect and smoothness of the reaction, it is 150 mL-400 mL. In the case of a mixed solvent, they are mixed at a conventionally known general proportion to make the total amount fall within the above-mentioned range.
The above-mentioned reaction is carried out in the presence of a base. Examples of the base include alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.), amine (triethylamine, etc.) and the like. Of these, alkali metal hydroxide is preferable. Particularly, sodium hydroxide and potassium hydroxide are preferable from the aspect of solubility in water. In addition, the amount of base to be used is generally 0.1 mol-1.0 mol relative to 1 mol of benzaldehyde (V-i). From the economic aspect and for the smooth progress of the reaction, it is preferably 0.2 mol-0.5 mol.
The above-mentioned reaction step is carried out generally at a temperature range of 40xc2x0 C.-100xc2x0 C. For sufficient reaction speed while suppressing a side reaction, a reaction in a temperature range of 55xc2x0 C.-75xc2x0 C. is preferable. This reaction is generally carried out in a reaction time of about 30 min-24 hr.
Step V-2
By reducing propyl styryl ketone (V-iii) obtained in the above-mentioned step V-1, 1-phenyl-3-hexanone (V) can be produced.
This reaction is generally carried out by adding a reduction catalyst to a solvent such as water, primary or secondary alcohols (e.g., methanol, ethanol, isopropanol, etc.), tertiary alcohols (e.g., tert-butanol, tert-amyl alcohol, etc.), aromatic compound (e.g., toluene, monochlorobenzene, etc.), esters (e.g., ethyl acetate, butyl acetate, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone) and the like, that do not inhibit the reaction or a mixed solvent thereof, preferably, ethyl acetate, THF, acetone or a mixed solvent thereof, and reacting propyl styryl ketone (V-iii) with hydrogen. It is also possible to use the reaction mixture after the above-mentioned step V-1 as a reaction solvent of this reduction reaction.
The reduction catalyst to be used for this reaction is exemplified by palladium carbon, palladium, palladium hydroxide, platinum oxide, platinum, platinum carbon, ruthenium oxide, ruthenium, ruthenium carbon and the like. Of these, palladium carbon and platinum oxide are preferable, and palladium carbon is particularly preferable. The amount of the reduction catalyst to be used is generally 2 g-20 g, preferably 4 g-10 g, relative to 1 mole of propyl styryl ketone (V-iii). When the amount of the reduction catalyst to be used is less than 2 g relative to 1 mole of propyl styryl ketone (V-iii), the reaction tends to become unpreferably slow, and when it exceeds 20 g, an effect corresponding to the amount to be used is not attained, which is economically unpreferable.
The amount of hydrogen to be used in this step is not particularly limited as long as it can reduce propyl styryl ketone (V-iii), and the reaction pressure is generally 50 kPa-1000 kPa, preferably 70 kPa-200 kPa, more preferably 90 kPa-150 kPa.
In this step, a base such as triethylamine, soda ash and the like may be added in an attempt to suppress a side reaction such as overreduction of 1-phenyl-3-hexanone (V), which is a product, and the like.
1-Phenyl-3-hexanone (V) [ketone (V)] obtained as above can be isolated by a conventional method. For example, the reduction catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to achieve isolation. The isolated ketone (V) can be purified by distillation under reduced pressure and the like. In addition, ketone (V) can be applied to the above-mentioned step (a) without purification.
Obtainment of ketone (V) to be used in the above-mentioned step (a) by the above-mentioned reaction is beneficial as compared to the method described in US publication 2002/0013501A and a method comprising oxidization of 1-phenyl-3-hexanol with hypochlorite (JP-A-2002-265409), because side reaction does not occur easily.
2. Step for Producing Racemic 3-hydroxy-3-(2-phenylethyl)hexanoic Acid [Step (b)]
This step is for producing 3-hydroxy-3-(2-phenylethyl)hexanoic acid [racemic carboxylic acid (II)] by hydrolysis of racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester [racemic carboxylic acid ester (VII)]. While the racemic carboxylic acid ester (VII) to be used for this step is not particularly limited, it is preferably obtained by the above-mentioned step (a).
The hydrolysis of the racemic carboxylic acid ester (VII) can be conducted according to a conventional method. For example, racemic carboxylic acid ester (VII) and alkali metal compound are reacted in a solvent to give a salt of racemic carboxylic acid (II), which is then neutralized with an acid as necessary to give racemic carboxylic acid (II).
The solvent to be used for step (b) may be, for example, methanol, ethanol, water and the like; or a mixed solvent thereof, preferably water.
The amount of the solvent to be used in step (b) is generally 1 L-10 L, preferably 1 L-5 L, per 1 kg of racemic carboxylic acid ester (VII).
The alkali metal compound to be used in step (b) is exemplified by sodium hydroxide and potassium hydroxide, with preference given to sodium hydroxide. The amount of the alkali metal compound to be used is generally 1.0 mole-10 moles, preferably 1.5 moles-2.5 moles, per 1 mole of racemic carboxylic acid ester (VII). When the amount of the alkali metal compound to be used is less than 1.0 mole relative to 1 mole of racemic carboxylic acid ester (VII), the reaction may not complete, which is unpreferable. When it is used in excess of 10 moles, an effect corresponding to the amount to be used is not attained, which is economically unpreferable. The alkali metal compound may be added to the reaction system as it is, but addition as an aqueous solution or alcohol solution is preferable. The amount of a solvent to be used for dissolving an alkali metal compound is included in the amount of the above-mentioned solvent to be used.
In step (b), the acid to be used for neutralization is exemplified by hydrochloric acid, sulfuric acid, phosphoric acid and the like and the amount of use thereof is such an amount as makes the pH of the reaction mixture generally not more than 7, preferably not more than 5.
In step (b), the reaction of the racemic carboxylic acid ester (VII) with an alkali metal compound depends on the kind of alkali metal compound and the amount thereof to be used and the like. The reaction is generally carried out at 15xc2x0 C.-100xc2x0 C., preferably 30xc2x0 C.-60xc2x0 C., and generally ends in 30 min-30 hr, preferably 1.5 hr-20 hr.
The racemic carboxylic acid (II) obtained in step (b) can be isolated and purified by a conventional method. For example, the reaction mixture is extracted with a solvent, washed and filtrated and the obtained filtrate is washed, dried and concentrated under reduced pressure to isolate racemic carboxylic acid (II).
The racemic carboxylic acid (II) obtained in step (b) is preferably used without purification, or as a solution of racemic carboxylic acid (II) leaving a part or the entirety of the extraction solvent in the isolation step, for step (c) to be mentioned below. That is, a solution of the extraction solvent of racemic carboxylic acid (II) obtained in step (b) is only partially concentrated and used in the following step (c) or used in (c) without concentration.
In this way, by using racemic carboxylic acid (II) as a solution leaving a part or the entirety of an extraction solvent in step (c) to be mentioned below, a step for concentration can be omitted, which is economically advantageous. In addition, a heat treatment for concentration can be avoided, and lower yield due to heat decomposition of racemic carboxylic acid (II) can be advantageously avoided.
As the extraction solvent, those used for optical resolution in step (c) to be mentioned below, such as one or more kinds of solvents selected from ethyl acetate, MIBK, methyl ethyl ketone, diisopropyl ether and THF, and the like are mentioned, with preference given to MIBK.
3. Step for Producing (R)-3-hydroxy-3-(2-phenylethyl)hexanoic Acid [Step (c)]
The step for producing (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid [(R)-carboxylic acid (III)] is characterized by the use of optically active amine of the formula 
wherein R2 is 3,4-dimethoxyphenyl or 2-chlorophenyl [optically active amine (VIII)], which is optically active, as an agent for the optical resolution of (R)-carboxylic acid (III) from racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid [racemic carboxylic acid (II)].
To be specific, the step is characterized by the use of (R)-N-(3,4-dimethoxybenzyl)-xcex1-phenylethylamine of the following formula (VIIIa) 
(hereinafter to be also referred to as xe2x80x9cdimethoxy form (VIIIa)xe2x80x9d), or (R)-N-(o-chlorobenzyl)-xcex1-phenylethylamine of the following formula (VIIIb) 
(hereinafter to be also referred to as xe2x80x9cchloro form (VIIIb)xe2x80x9d), as an agent for optical resolution.
In the following, dimethoxy form (VIIIa) and chloro form (VIIIb) may be simply referred to generally as xe2x80x9coptically active amine (VIII)xe2x80x9d, without particular distinction.
According to such step (c), (R)-carboxylic acid (III) having an optical purity of not less than 97% e.e. can be obtained in the total yield of not less than 34% by the use of the above-mentioned optically active amine (VIII) as an agent for optical resolution. Particularly, when dimethoxy form (VIIIa) wherein R2 is 3,4-dimethoxyphenyl is used, (R)-carboxylic acid (III) having not less than 99% e.e. can be obtained in the total yield of not less than 34%. As described above, the production method of the present invention can afford a salt of (R)-carboxylic acid (III) having the same level or high level of optical purity in the total yield of not less than about 1.3 fold, as compared to conventional optical resolution of (R)-carboxylic acid (III) using (xe2x88x92)-norephedrine. Such method strikingly improves industrial production efficiency of (R)-carboxylic acid (III) as compared to conventional cases.
As used herein, by xe2x80x9cthe total yieldxe2x80x9d is meant the yield (yield of the objective highly optically pure (R)-carboxylic acid (III) relative to racemic carboxylic acid (II)) throughout the reaction system, as mentioned above, which is to be distinguished from the yield in individual reactions in the reaction system (in the following, a simple reference to a xe2x80x9cyieldxe2x80x9d means xe2x80x9ca ratio of the amount of the resulting product actually produced from the starting material immediately before the reaction for producing the resulting product, relative to the theoretical amount of production of the resulting productxe2x80x9d).
As used herein, the optical purity is a value determined by high performance liquid chromatography (HPLC) to be mentioned below.
By this production method, racemic carboxylic acid (II) and the above-mentioned optically active amine (VIII) are specifically mixed in a solvent to allow crystallization (crystal precipitation) to give a salt of (R)-carboxylic acid (III) with optically active amine. The racemic carboxylic acid (II) to be used for this step is not particularly limited, but one produced by the above-mentioned step (b) is preferable.
The racemic carboxylic acid (II) and the optically active amine (VIII) are preferably mixed at a ratio of 1:0.5-1:1 (molar ratio), more preferably 1:0.8-1:1 (molar ratio), to economically achieve higher yield and higher optical purity. When the amount of optically active amine (VIII) to be used is less than 0.5 mole relative to 1 mole of racemic carboxylic acid (II), the optical purity tends to increase, but the yield tends to unpreferably decrease. When the amount of optically active amine (VIII) to be used exceeds 1 mole relative to 1 mole of racemic carboxylic acid (II), filtration property of the salt tends to be degraded. In addition, yield and optical purity do not show any particular changes, which is economically unpreferably useless.
The solvent to be used for the above-mentioned mixing of racemic carboxylic acid (II) and optically active amine (VIII) is exemplified by one or more kinds of solvents selected from ethyl acetate, methanol, isopropanol, ethanol, acetonitrile, MIBK, acetone, methyl ethyl ketone, diisopropyl ether, dimethoxyethane and THF. These solvents may further contain water. From the aspects of the yield and optical purity of the salt, and safety, one or more kinds of the solvents selected from ethyl acetate, methanol, isopropanol, ethanol, MIBK, diisopropyl ether and THF from among the above-mentioned are particularly preferable. Moreover, from the aspect of the extraction solvent in the above-mentioned step (b), one or more kinds of solvents selected from ethyl acetate, MIBK, methyl ethyl ketone, diisopropyl ether and THF, particularly MIBK, are particularly preferable. The use of these solvents further containing water is preferable.
As mentioned above, as the solvent to be used for the above-mentioned mixing of racemic carboxylic acid (II) and the above-mentioned optically active amine (VIII), a part or the entirety of the extraction solvent of the above-mentioned step (b) is preferably left and used. That is, a part or the entirety of the extraction solvent for racemic carboxylic acid (II) obtained in the above-mentioned step (b) is left upon partially concentration or without concentration, and the optical resolution is preferably conducted in the solvent containing the above-mentioned solvent as necessary.
The amount of the above-mentioned solvent to be used is free of any particular limitation. For a salt to be obtained in a higher yield with a higher optical purity, it is preferably 5 L-20 L, more preferably 8 L-16 L, relative to 1 kg of racemic carboxylic acid (II). When the amount of the solvent to be used is less than 5 L relative to 1 kg of racemic carboxylic acid (II), heating during production of the salt may fail to dissolve the resulting salt, which unpreferably lowers the optical purity. When the amount of the solvent to be used exceeds 20 L relative to 1 kg of racemic carboxylic acid (II), the amount of the salt that dissolves in the solvent tends to increase and lower the yield, which is unpreferable.
When the above-mentioned solvent is a mixed solvent (inclusive of a mixture with water), the solvents are mixed in a conventionally known general and optional ratio to achieve the above-mentioned ranges of the amounts to be used. When the racemic carboxylic acid (II) is used as a solution of an extraction solvent of the above-mentioned step (b), the amount of the extraction solvent is included in the amount of the solvent to be used for optical resolution.
The aforementioned racemic carboxylic acid (II) and optically active amine (VIII) are mixed by adding optically active amine (VIII) to a solution of racemic carboxylic acid (II) dissolved in advance in a general solvent or a solution of the extraction solvent in step (b). Stirring the mixture after the addition results in the precipitation of the salt. Therefore, the mixture is generally heated to 50xc2x0 C.-100xc2x0 C. and stirred to dissolve the salt. When dissolution of the salt is insufficient by stirring at the raised temperature, the solvent may be further added until the salt is dissolved. The solvent to be further added here is similar to the aforementioned solvents.
The crystallization of a salt of (R)-carboxylic acid (III) with optically active amine (VIII) includes stirring with cooling until the salt is precipitated after the above-mentioned stirring at a raised temperature. Then, the mixture is gradually cooled, and after stirring further at a given temperature (e.g., 25xc2x0 C.), the mixture is filtrated, washed with a solvent and stirred to give a highly optically pure amine salt of (R)-carboxylic acid (III) in the aforementioned yield.
During stirring with cooling until the salt is sufficiently precipitated, the crystal precipitation temperature is generally not more than 50xc2x0 C., preferably 0xc2x0 C.-30xc2x0 C., and the stirring time is generally 0.5 hr-20 hr.
The solvent to be used after filtration is preferably a solvent having the solvent composition used for crystal precipitation. The amount of the solvent to be used for washing is not particularly limited and is an amount sufficient for washing the filtrate.
The production method of the present invention may be realized by gradually adding a solution of optically active amine (VIII) to a solution of racemic carboxylic acid (II) at room temperature (20xc2x0 C.)-50xc2x0 C. to allow gradual precipitation of the salt, and allowing the mixture to cool. By this method, the amount of the solvent to be used can be advantageously reduced as compared to the above-mentioned method, because the salt does not need to be dissolved completely once.
For recrystallization, the solvent to be used for dissolving a salt of (R)-carboxylic acid (III) can be similar to that used for dissolving racemic carboxylic acid (II) in the above-mentioned optical resolution, wherein the preferable solvent is the same. The amount of these solvents to be used for this reaction is free of any particular limitation, but it is preferably 4 L-20 L, more preferably 5 L-15 L, particularly preferably 8 L-15 L, relative to 1 kg of a salt of (R)-carboxylic acid (III), because high yield and high optical purity can be achieved. When the amount of the above-mentioned solvent to be used is less than 4 L relative to 1 kg of a salt of (R)-carboxylic acid (III), the salt may be difficult to dissolve, unpreferably making high optical purity difficult to achieve and stirring for cooling also difficult. When it exceeds 20 L, the amount of the dissolved salt tend to increases to unpreferably cause lower yield.
After mixing a salt of (R)-carboxylic acid (III) with the above-mentioned solvent, the mixture is generally heated to a temperature range of 50xc2x0 C.-100xc2x0 C. to dissolve the salt.
After dissolution of the salt of (R)-carboxylic acid (III), this solution is gradually cooled and seed crystals are added at a suitable temperature (e.g., 40xc2x0 C.-80xc2x0 C.), followed by stirring. The time of the stirring is generally about 10 min-5 hr. Further, the mixture is gradually generally cooled to 0xc2x0 C.-40xc2x0 C., preferably 0xc2x0 C.-30xc2x0 C., over 60 min-24 hr.
Then, the mixture is stirred further at a given temperature (e.g., 25xc2x0 C.), filtrated, washed with a solvent and dried. The solvent to be used for filtration and washing is desirably similar to that used for crystal precipitation. The obtained filtrate may be mixed with the aforementioned salt of optically active amine (VIII) with racemic carboxylic acid (II) and used again for optical resolution.
The obtained amine salt of (R)-carboxylic acid (III) can be decomposed into (R)-carboxylic acid (III) and optically active amine (VIII) by a conventional method. For example, amine salt of (R)-carboxylic acid (III) is decomposed in an organic solvent (e.g., ethyl acetate, etc.) with, for example, aqueous caustic alkali solution, aqueous alkali carbonate solution or aqueous sodium bicarbonate, leaving the optically active amine in the organic layer, and using, for example, an inorganic acid such as hydrochloric acid, sulfuric acid and the like, the aqueous layer is made acidic and extracted with an organic solvent to give (R)-carboxylic acid (III).
Alternatively, an amine salt of (R)-carboxylic acid (III) may be decomposed with aqueous acid solution (e.g., inorganic acid such as hydrochloric acid, sulfuric acid etc., and the like) in an organic solvent (e.g., toluene, ethyl acetate, MIBK, or a mixed solvent of these with heptane) and extracted with the organic solvent to give (R)-carboxylic acid (III). In this case, optically active amine (VIII) can be obtained as an aqueous salt solution of the acid used for the above-mentioned decomposition of the amine salt.
The optically active amine (VIII) used for optical resolution is preferably recovered from the mother liquor of the optical resolution or crystal salt of (R)-carboxylic acid (III) with optically active amine (VIII) (hereinafter to be also referred to as xe2x80x9csalt with carboxylic acid and the likexe2x80x9d).
As used herein, the recovery from the mother liquor of the optical resolution means a recovery of optically active amine (VIII) from a salt of (S) rich carboxylic acid (II) with optically active amine (VIII).
Furthermore, the recovery from a salt of (R)-carboxylic acid (III) with optically active amine (VIII) means a recovery of optically active amine (VIII) produced by the decomposition of a salt of (R)-carboxylic acid (III) with optically active amine (VIII).
A method for recovering optically active amine (VIII) from a salt with carboxylic acid and the like may be a conventional method. For example, a filtrate-washing mixture containing a salt of (S) rich 3-hydroxy-3-(2-phenylethyl)hexanoic acid with optically active amine (VIII) or a salt of (R)-carboxylic acid (III) with optically active amine (VIII) is decomposed with aqueous caustic alkali solution, aqueous alkali carbonate solution or aqueous sodium bicarbonate in an organic solvent (e.g., toluene, ethyl acetate, MIBK, or a mixed solvent of these with heptane) to recover optically active amine (VIII) as a solution in an organic solvent layer.
In addition, a filtrate-washing mixture containing a salt of (S) rich 3-hydroxy-3-(2-phenylethyl)hexanoic acid with optically active amine (VIII) or a salt of (R)-carboxylic acid (III) with optically active amine (VIII) is decomposed with an aqueous acid solution (e.g., inorganic acid such as hydrochloric acid, sulfuric acid etc., and the like) in an organic solvent (e.g., toluene, ethyl acetate, MIBK, or a mixed solvent of these with heptane) to recover an aqueous acid solution of optically active amine (VIII) with the acid used for the above-mentioned decomposition of the amine salt. Moreover, after treatment of the aqueous layer with aqueous caustic alkali solution, aqueous alkali carbonate solution or aqueous sodium bicarbonate and the like, it is extracted with an organic solvent (e.g., toluene, ethyl acetate, MIBK, or a mixed solvent of these with heptane) to give optically active amine (VIII) solution of an organic solvent.
The recovered optically active amine (VIII) can be isolated and purified by a conventional method. For example, an organic solvent layer containing the optically active amine (VIII) is washed with water and concentrated to isolate optically active amine (VIII). After isolation, it is purified by distillation under reduced pressure or the recovered optically active amine (VIII) solution of an organic solvent may be subjected to optical resolution without purification.
Using the optically active amine (VIII) recovered as mentioned above, the optically active amine (VIII) can be used repeatedly and the process is economical than new synthesis. Therefore, (R)-carboxylic acid (III) can be produced at a lower cost.
The (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid [(R)-carboxylic acid (III)] obtained as above is considered to be extremely useful as a synthetic intermediate for the anti-HIV agent, PNU-140690. The derivatization from (R)-carboxylic acid (III) into PNU-140690 can be done as described in, for example, the above-mentioned reference (J. Org. Chem., Vol. 63, No. 21, 1998, 7348-7356).
In addition, (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoic acid ester can be produced by the method proposed below by the present inventors using (R)-carboxylic acid (III).
Production Method of Optically Active Amine (VIII)
(i) Method 1
The optically active amine (VIII) to be used in the above-mentioned step (c) is preferably obtained by the following method proposed by the present inventors.
That is, as shown in the following scheme, a compound of the formula (VIII-i) (hereinafter to be also referred to as xe2x80x9ccompound (VIII-i)xe2x80x9d) and (R)-1-phenylethylamine of the formula (VIII-ii) (hereinafter to be also referred to as xe2x80x9c(R)-amine (VIII-ii)xe2x80x9d) are condensed to give an imine compound of the formula (VIII-iii) (hereinafter to be also referred to as xe2x80x9cimine compound (VIII-iii)xe2x80x9d) (step VIII-1), after which it is reduced (step VIII-2) to give optically active amine (VIII). 
wherein R2 is as defined above.
The production method of optically active amine (VIII) is explained in the following.
The imine compound (VIII-iii) in the above-mentioned reaction can be obtained by condensation of compound (VIII-i) and (R)-amine (VIII-ii) (step VIII-1). In this condensation reaction, (R)-amine (VIII-ii) is generally used in an amount of 80 mol %-100 mol %, preferably 90 mol %-100 mol %, of compound (VIII-i).
The solvent in step VIII-1 is not subject to any particular limitation as long as it does not inhibit the reaction. Generally, methanol, ethanol, isopropanol, toluene and the like, preferably methanol, isopropanol, toluene and the like or a mixed solvent thereof are used. The above-mentioned solvent is generally used in an amount of 100 mL-500 mL relative to 1 mole of compound (VIII-i), which is preferably 200 mL-400 mL from the economic aspect and for the smooth progress of the reaction. In the case of a mixed solvent, they are mixed at a conventionally known general proportion to make the total amount fall within the above-mentioned range.
The step VIII-1 is carried out generally in a temperature range of 25xc2x0 C.-80xc2x0 C. For sufficient reaction speed while suppressing a side reaction, a reaction in a temperature range of 30xc2x0 C.-60xc2x0 C. is preferable. This reaction is generally carried out in a reaction time of about 15 min-10 hr.
The imine compound (VIII-iii) thus obtained is reduced to give optically active amine (VIII) (step VIII-2). This reaction is generally carried out by adding a reduction catalyst to the hydrogenation reaction mixture after the above-mentioned step VIII-1 to allow hydrogenation reaction of imine compound (VIII-iii) with hydrogen to give the optically active amine (VIII).
The reduction catalyst is exemplified by palladium carbon, palladium, palladium hydroxide, platinum oxide, platinum, platinum carbon, ruthenium oxide, ruthenium, ruthenium carbon and the like. Preferred are palladium carbon and platinum oxide, and more preferred is palladium carbon. The amount of the reduction catalyst to be used is generally 1 g-10 g, preferably 1.5 g-5.0 g, relative to 1 mole of compound (VIII-i). When the amount of the reduction catalyst to be used is less than 1 g relative to 1 mole of compound (VIII-i), the reaction tends to become unpreferably slow, and when it exceeds 10 g, an effect corresponding to the amount to be used is not attained, which is economically unpreferable.
The amount of the hydrogen to be used in step VIII-2 is no particularly limited as long as it can reduce the imine compound (VIII-iii). The reaction pressure is generally 100 kPa-3000 kPa, preferably 100 kPa-2000 kPa, more preferably 200 kPa-1500 kPa.
In step VIII-2, a base such as triethylamine, soda ash and the like is preferably added to suppress a side reaction such as hydrogenolysis of optically active amine (VIII), and the like. The amount of the base to be added is generally 0.1 g-10 g, preferably 1 g-3 g, relative to 1 g of the reduction catalyst. When the amount of the base is less than 0.1 g relative to 1 g of the reduction catalyst, side reaction such as hydrogenolysis of optically active amine (VIII) and the like unpreferably may not be sufficiently suppressed. When it exceeds 10 g, the reduction catalyst is possibly inactivated to make the reaction slow, which is unpreferable.
The recovered optically active amine (VIII) obtained in step VIII-2 can be isolated and purified by a conventional method. For example, a reduction catalyst is removed by filtration and then the filtrate is concentrated under reduced pressure for isolation. The isolated optically active amine (VIII) can be purified by distillation under reduced pressure and the like. The optically active amine (VIII) may be subjected to the above-mentioned step (c) without purification.
The above-mentioned reduction during production of optically active amine (VIII) used in the above-mentioned step (c) is economical as compared to reduction using a reducing agent such as sodium borohydride and the like, because a reducing agent does not need to be used in a stoichiometric amount and the reduction catalyst can be used repeatedly. In addition, complicated manipulation such as decomposition of the reducing agent and the like is not necessary and a convenient operation of filtration of the reduction catalyst and concentration of filtrate is sufficient, thus advantageously making the step efficient.
(ii) Method 2
The dimethoxy form (VIIIa) [(R)-N-(3,4-dimethoxybenzyl)-xcex1-phenylethylamine] of the optically active amine (VIII) used in step (c) of the present invention can be also obtained as in the following.
First, (R)-1-phenylethylamin is added while heating 3,4-dimethoxybenzaldehyde solution to about 40xc2x0 C.-60xc2x0 C. The solvent to dissolve 3,4-dimethoxybenzaldehyde is free of particular limitation and exemplified by methanol, isopropanol, ethanol and the like. It is preferable that the amount of (R)-1-phenylethylamine to be added is in a proportion of 90 mol %-100 mol % of 3,4-dimethoxybenzaldehyde.
After the addition of (R)-1-phenylethylamine, the mixture is stirred with heating for about 0.5 hr-2 hr and cooled to 20xc2x0 C.-35xc2x0 C., after which sodium borohydride is added. In view of the reactivity, sodium borohydride is preferably added in a proportion of about 1:0.5 (molar ratio) relative to 1 mole of 3,4-dimethoxybenzaldehyde.
After the above-mentioned reaction, the mixture is extracted with toluene and the like, washed and concentrated by a method known per se to give (R)-N-(3,4-dimethoxybenzyl)-xcex1-phenylethylamine.
A chloro form (VIIIb)[(R)-N-(o-chlorobenzyl)-xcex1-phenylethylamine] of the optically active amine (VIII) can be obtained in the same manner as in the aforementioned synthetic method of dimethoxy form (VIIIa) except that 2-chlorobenzaldehyde is used instead of 3,4-dimethoxybenzaldehyde.
4. Production Method of (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoic Acid Ester
This method is, as shown in the following scheme, a production method comprising reacting (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid [(R)-carboxylic acid (III)], a halogenating agent and an imidazole compound of the formula (iv) (hereinafter to be also referred to as xe2x80x9cimidazole compound (iv)xe2x80x9d) in the presence of a base to give an imidazolide of the formula (IX) (hereinafter to be also referred to as xe2x80x9cimidazolide (IX)xe2x80x9d), which imidazolide (IX) obtained is reacted with malonic acid monoester of the formula (v) (hereinafter to be also referred to as xe2x80x9cmalonic acid monoester (v)xe2x80x9d) in the presence of a divalent metal salt and treated with an acid to give (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoic acid ester of the formula (X) (hereinafter to be also referred to as xe2x80x9c(R)-carboxylic acid ester (X)xe2x80x9d). The (R)-carboxylic acid (III) to be used for this method is not particularly limited and one obtained according to the method described in J. Org. Chem., Vol. 63, No. 21, 1998, p7348-7356 and the like, with preference given to one produced by the above-mentioned step (c). 
wherein R1b, R2b and R3b are the same or different and each is hydrogen atom or organic group, and R1c and R2c are free of particular limitation as long as they do not influence the reaction.
This method can be applied to a produce method xcex2-ketoester other than (R)-carboxylic acid ester (X) from a carboxylic acid other than (R)-carboxylic acid (III). The production method is explained in the following including the production of xcex2-ketoester other than (R)-carboxylic acid ester (X).
As shown in the following scheme, carboxylic acid of the formula (vi) (hereinafter to be also referred to as xe2x80x9ccarboxylic acid (vi)xe2x80x9d) such as (R)-carboxylic acid (III), a halogenating agent and an imidazole compound (iv) are reacted in the presence of a base to give imidazolide of the formula (vii) (hereinafter to be also referred to as xe2x80x9cimidazolide (vii)xe2x80x9d) and the obtained imidazolide (vii) is reacted with malonic acid monoester (v) in the presence of a divalent metal salt, and treat with an acid to give xcex2-ketoester of the formula (viii) (hereinafter to be also referred to as xe2x80x9cxcex2-ketoester (viii)xe2x80x9d), such as (R)-carboxylic acid ester (X). The xcex2-ketoester (viii) obtained by this method is a useful intermediate for a pharmaceutical product, pesticide and the like. 
wherein R1d is an organic group and R1b, R2b, R3b, R1c and R2c are as defined above.
The xe2x80x9corganic groupxe2x80x9d for R1d of the formula (vi) in the above-mentioned production method is exemplified by alkyl group optionally having substituents, cycloalkyl group optionally having substituents, aryl group optionally having substituents, aralkyl group optionally having substituents, heteroaryl group optionally having substituents and the like.
As the xe2x80x9calkyl groupxe2x80x9d of the above-mentioned xe2x80x9calkyl group optionally having substituentsxe2x80x9d, straight or branched chain alkyl group having 1-20 carbon atoms is mentioned. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like. Preferably, straight or branched chain alkyl group having 1-12 carbon atoms, such as, ethyl, heptyl, heptadecyl, 3-heptyl and the like can be mentioned. The alkyl group may have a double bond or a triple bond, and examples thereof include allyl, propinyl and the like.
The xe2x80x9ccycloalkyl groupxe2x80x9d of the above-mentioned xe2x80x9ccycloalkyl group optionally having substituentsxe2x80x9d is exemplified by cycloalkyl group having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, cycloalkyl group having 3-6 carbon atoms, such as, cyclopropyl, cyclohexyl and the like can be mentioned.
The xe2x80x9caryl groupxe2x80x9d of the above-mentioned xe2x80x9caryl group optionally having substituentsxe2x80x9d is exemplified by aryl group having carbon atoms 6-18, such as, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and the like. Preferably, aryl group having carbon atoms 6-12, such as phenyl, 2-naphthyl and the like can be mentioned.
As regards xe2x80x9caralkyl groupxe2x80x9d of the above-mentioned xe2x80x9caralkyl group optionally having substituentsxe2x80x9d, aralkyl group having 7-20 carbon atoms can be mentioned, wherein the aryl moiety is the same as the above-mentioned xe2x80x9caryl groupxe2x80x9d, and the alkyl moiety is a straight or branched chain alkyl group having 1-14 carbon atoms. Examples thereof include benzyl, 1-phenethyl, 2-phenylethyl, 2-(2-phenylethyl)pentyl and the like. Preferred is aralkyl group having 7-16 carbon atoms, such as, 2-phenylethyl, 2-(2-phenylethyl)pentyl and the like. The alkyl moiety of this aralkyl group may have a double bond or triple bond, and examples of such aralkyl group include styryl and the like.
The xe2x80x9cheteroaryl groupxe2x80x9d of the above-mentioned xe2x80x9cheteroaryl group optionally having substituentsxe2x80x9d is exemplified by a 5-membered-13-membered heteroaryl ring having one or more hetero atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom and 3-12 carbon atoms. Examples thereof include pyridyl, quinolyl, isoquinolyl, thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like, with preference given to 6-membered-13-membered heteroaryl ring group having one nitrogen atom and 5-9 carbon atoms, such as, pyridyl, quinolyl and the like.
These groups may have a substituent that does not inhibit this reaction, such as hydroxyl group, halogen atom (e.g., chlorine atom, fluorine atom, bromine atom, iodine atom, etc.), alkoxy group having 1-6 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.), alkoxycarbonyl group having 2 to 8 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, etc.), nitro group, oxo group, nitrile group, amide group having 1-8 carbon atoms (e.g., formamide, acetamide, propionamide, butylamide, pentaneamide, hexaneamide, heptanamide, octaneamide, benzamide, etc.), as well as the above-defined xe2x80x9calkyl groupxe2x80x9d, xe2x80x9ccycloalkyl groupxe2x80x9d, xe2x80x9caryl groupxe2x80x9d, xe2x80x9caralkyl groupxe2x80x9d and xe2x80x9cheteroaryl groupxe2x80x9d and the like. While the number of the substituent is not particularly limited, but it is preferably 1-3, which may be the same or different.
Preferable examples of carboxylic acid (vi) in the above-mentioned production method are shown in the following.
(1) The carboxylic acid having the above-mentioned xe2x80x9calkyl group optionally having substituentsxe2x80x9d is exemplified by propionic acid, capric acid, stearic acid, 2-ethylhexanoic acid and the like.
(2) The carboxylic acid having the above-mentioned xe2x80x9ccycloalkyl group optionally having substituentsxe2x80x9d is exemplified by, cyclopropanoic acid, cyclohexanoic acid and the like.
(3) The carboxylic acid having the above-mentioned xe2x80x9caryl group optionally having substituentsxe2x80x9d is exemplified by benzoic acid, 4-hydroxybenzoic acid, naphthalene-2-carboxylic acid, 4-chlorobenzoic acid and the like.
(4) The carboxylic acid having the above-mentioned xe2x80x9caralkyl group optionally having substituentsxe2x80x9d is exemplified by 3-phenylpropionic acid, 2-cyclohexyl-2-hydroxy-2-phenylacetic acid, cinnamic acid, 3-(2-phenylethyl)hexanoic acid, 3-hydroxy-3-(2-phenylethyl)hexanoic acid and the like.
(5) The carboxylic acid having the above-mentioned xe2x80x9cheteroaryl group optionally having substituentsxe2x80x9d is exemplified by 2-chloronicotinic acid, 2,6-dichloro-5-fluoronicotinic acid, quinoline-3-carboxylic acid and the like.
Of these, 3-hydroxy-3-(2-phenylethyl)hexanoic acid (particularly an (R) isomer thereof), 2,6-dichloro-5-fluoronicotinic acid, cinnamic acid, 4-hydroxybenzoic acid and the like are preferable because they can produce xcex2-ketoester useful as an intermediate for a pharmaceutical agent.
The xe2x80x9cimidazole compoundxe2x80x9d in the above-mentioned production method refers to a compound wherein the hydrogen atom bonded to the carbon of imidazole is optionally substituted by an organic group, such as, imidazole, 2-methylimidazole and the like, with preference given to imidazole.
The xe2x80x9corganic groupxe2x80x9d for R1b, R2b and R3b of the above-mentioned formula (iv) is exemplified by alkyl group, cycloalkyl group, aryl group, aralkyl group and the like.
As the aforementioned xe2x80x9calkyl groupxe2x80x9d, straight or branched chain alkyl having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned.
The aforementioned xe2x80x9ccycloalkyl groupxe2x80x9d is exemplified by cycloalkyl group having 3-6 carbon atoms, such as, cyclopropyl, cyclobutyl, cyclopentyl and the like.
The aforementioned xe2x80x9caryl groupxe2x80x9d is exemplified by phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl and the like.
The aforementioned xe2x80x9caralkyl groupxe2x80x9d is exemplified by benzyl, phenethyl, phenylpropyl and the like.
The aforementioned xe2x80x9chalogenating agentxe2x80x9d is not particularly limited and is exemplified by thionyl chloride, thionyl bromide, phosgene, diphosgene, triphosgene and the like, with preference given to thionyl chloride.
The xe2x80x9cbasexe2x80x9d in the above-mentioned method is exemplified by aliphatic tertiary amines (e.g., trimethylamine, triethylamine, tributylamine, diisopropylethylamine and the like), aromatic tertiary amines (e.g., pyridine, picoline, 2,6-lutidine, collidine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline and the like) or alkali metal carbonate (e.g., sodium carbonate, potassium carbonate and the like). Preferred is triethylamine or sodium carbonate and particularly preferred is triethylamine.
The xe2x80x9cmalonic acid monoester (v)xe2x80x9d to be used for the above-mentioned method is free of particular limitation and is exemplified by malonic acid monoalkylester, or a compound of the formula (v) wherein R1c is straight or branched chain alkyl group having 1-6 carbon atoms (e.g., methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), preferably straight or branched chain alkyl group having 1-4 carbon atoms (e.g., ethyl, isopropyl, tert-butyl, etc.) and R2c is hydrogen atom or monovalent metal atom, preferably, alkali metal atom (e.g., sodium, potassium, etc.). Specifically, potassium ethyl malonate, sodium ethyl malonate, potassium isopropyl malonate, potassium tert-butyl malonate and the like are mentioned. In view of easiness of obtainment, potassium ethyl malonate is preferably used.
The xe2x80x9cdivalent metal saltxe2x80x9d in the above-mentioned method is preferably magnesium chloride.
The xe2x80x9cacidxe2x80x9d in the above-mentioned method is exemplified by mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like), organic acids (e.g., acetic acid, propionic acid, methanesulfonic acid, toluenesulfonic acid and the like) and the like, with preference given to hydrochloric acid.
In the above-mentioned method, by xe2x80x9ctreated with an acidxe2x80x9d is meant addition of an acid to a reaction mixture or addition of a reaction mixture to an acid to changing the liquid property of the reaction mixture from neutral to weak acidic.
Step viii-1
A reaction to produce imidazolide (vii) is realized by reacting carboxylic acid (vi), a halogenating agent and imidazole compound (iv) in a solvent in the presence of a base.
In the above-mentioned reaction, the order of addition of reagents is not particularly limited and, for example, halogenating agent is added to a mixture of imidazole compound (iv) and carboxylic acid (vi) charged in a solvent in advance in the presence of a base; after adding a halogenating agent to imidazole compound (iv) charged in a solvent in the presence of a base, carboxylic acid (vi) is further added; or after adding a mixture of a base and imidazole compound (iv) to a halogenating agent charged in a solvent, carboxylic acid (vi) is further added and the like.
In the above-mentioned reaction, the amount of imidazole compound (iv) to be used is preferably 1 mole-3 moles relative to 1 mole of carboxylic acid (vi), which is more preferably 1.1 moles-2.2 moles from the economic aspect. In the above-mentioned reaction, when the amount of imidazole compound (iv) to be used is less than 1 mole relative to 1 mole of carboxylic acid (vi), reaction efficiency may reduce because carboxylic acid (vi) remains partly unreacted. In the above-mentioned reaction, the use of imidazole compound (iv) in excess of 3 moles relative to 1 mole of carboxylic acid (vi) is economically unpreferable because imidazole compound (iv) not involved in the reaction exists in a large amount.
In the above-mentioned reaction, the amount of the halogenating agent to be used is preferably 1 mole-1.1 moles relative to 1 mole of carboxylic acid (vi), which is more preferably 1.01 moles-1.05 moles from the economic aspect. In the above-mentioned reaction, when the amount of halogenating agent to be used is less than 1 mole relative to 1 mole of carboxylic acid (vi), the reaction efficiency may reduce because carboxylic acid (vi) remains partly unreacted. In the above-mentioned reaction, when the amount of halogenating agent to be used exceeds 1.1 moles relative to 1 mole of carboxylic acid (vi), a large amount of halogenating agent unnecessary for the reaction with carboxylic acid (vi) is used, which is not only economically unpreferable but may cause side reaction such as dehydrating reaction, elimination reaction and the like, because halogenating agent remains in the resulting product.
In the above-mentioned reaction, the amount of base to be used is preferably 1 mole-3 moles relative to 1 mole of carboxylic acid (vi), which is more preferably 1.1 moles-2.5 moles from the economic aspect. In the above-mentioned reaction, when the amount of base to be used is less than 1 mole relative to 1 mole of carboxylic acid (vi), the reaction efficiency may reduce because carboxylic acid (vi) remains partly unreacted. In addition, the reaction mixture may become acidic and the side reaction such as dehydrating reaction, elimination reaction and the like may be caused. In the above-mentioned reaction, moreover, when the amount of base to be used exceeds 3 moles relative to 1 mole of carboxylic acid (vi), a large amount of base unnecessary for the reaction with carboxylic acid (vi) is used, which is economically unpreferable.
The above-mentioned reaction is carried out generally within a temperature range of xe2x88x9225xc2x0 C.-0xc2x0 C., preferably xe2x88x9220xc2x0 C.-xe2x88x9210xc2x0 C. When the reaction temperature is less than xe2x88x9225xc2x0 C., the reaction may proceed slowly, or the reaction may not proceed at all, and when the reaction temperature exceeds 0xc2x0 C., carboxylic acid (vi), which is a starting material, may be decomposed in the reaction mixture, or imidazolide (vii), which is a resulting product, may be decomposed to reduce the reaction yield.
The reaction time of the above-mentioned reaction is not particularly limited and the reaction completes generally in 30 min-1 hr.
The solvent to be used for the above-mentioned reaction may be any as long as it does not inhibit the reaction and ethers such as THF, dioxane, dimethoxyethane and the like, or a mixed solvent of the ethers with any solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene and the like, aliphatic hydrocarbons such as heptane, hexane, octane and the like can be preferably used. In the case of a mixed solvent, they are mixed at a conventionally known general proportion to make the total amount fall within the above-mentioned range.
The amount of the solvent to be used is generally 800 mL-4500 mL relative to 1 mole of carboxylic acid (vi), which is preferably 1000 mL-3000 mL for the smooth progress of the reaction and enhanced productivity.
Imidazolide (vii) can be isolated and purified by a known isolation method (e.g., extraction, drying and the like) and by a known purification method (e.g., crystallization and the like), or may be used as it is in a reaction mixture without isolation and purification.
Step viii-2
Imidazolide (vii) obtained as mentioned above, for example, is reacted with malonic acid monoester (v) in a solvent in the presence of a divalent metal salt [step viii-2-1], and treated with an acid [step viii-2-2] to give xcex2-ketoester (viii).
Step viii-2-1
In this step, the order of addition of reagents is not particularly limited and, for example, imidazolide (vii) is added to a mixture of malonic acid monoester (v) and divalent metal salt charged in a solvent in advance or malonic acid monoester (v) is added to a mixture of imidazolide (vii) and divalent metal salt charged in a solvent in advance and the like.
In this step, the amount of malonic acid monoester (v) to be used is preferably 1 mole-2 moles relative to 1 mole of imidazolide (vii), which is more preferably 1.3 moles-1.6 moles from the economic aspect. In the above-mentioned step viii-2-1, when the amount of malonic acid monoester (v) to be used is less than 1 mole relative to 1 mole of imidazolide (vii), the reaction efficiency may reduce because imidazolide (vii) remains partly unreacted. In the above-mentioned step viii-2-1, the use of malonic acid monoester (v) in excess of 2 moles relative to 1 mole of imidazolide (vii) is economically unpreferable because malonic acid monoester (v) not involved in the reaction exists in a large amount.
In this step, the amount of divalent metal salt to be used is preferably 1 mole-2 moles relative to 1 mole of malonic acid monoester (v), which is more preferably 1.1 moles-1.5 moles from the economic aspect. In the above-mentioned step viii-2-1, when the amount of divalent metal salt to be used is less than 1 mole relative to 1 mole of malonic acid monoester (v), the reaction efficiency may reduce because malonic acid monoester (v) remains partly unreacted. In the above-mentioned step viii-2-1, the use of divalent metal salt in excess of 2 moles relative to 1 mole of malonic acid monoester (v) is economically unpreferable, because a large amount of divalent metal salt not necessary for the reaction with malonic acid monoester (v) is present.
This step is carried out generally within a temperature range of 20xc2x0 C.-70xc2x0 C., preferably 40xc2x0 C.-60xc2x0 C. When the reaction temperature is less than 20xc2x0 C., the reaction may proceed slowly, or the reaction may not proceed at all, and when the reaction temperature exceeds 70xc2x0 C., imidazolide (vii), which is a starting material, may be decomposed in the reaction mixture to reduce the reaction yield.
The reaction time of the above-mentioned reaction is not particularly limited and the reaction completes generally in 4 hr-10 hr.
Step viii-2-2
In this step, an acid may be added to the reaction mixture in the above-mentioned step viii-2-1, or the reaction mixture in step viii-2-1 may be added to an acid.
In this step, the amount of the acid is preferably 2 moles-4 moles relative to 1 mole of imidazolide (vii), which is more preferably 2.3 moles-3 moles from the economic aspect. In the above-mentioned step viii-2-2, when the amount of acid is less than 2 moles relative to 1 mole of imidazolide (vii), decarbonation reaction may not proceed sufficiently, and the reaction efficiency may decrease. In the above-mentioned step viii-2-2, when the amount of acid to be used exceeds 4 moles relative to 1 mole of imidazolide (vii), the reaction mixture may come to have strong acidity and a side reaction such as racemization, elimination reaction and the like of the resulting product may occur.
This step is carried out generally within a temperature range of xe2x88x9210xc2x0 C.-40xc2x0 C., preferably 0xc2x0 C.-20xc2x0 C. When the reaction temperature is less than xe2x88x9210xc2x0 C., the reaction may proceed slowly, or the reaction may not proceed at all, and when the reaction temperature exceeds 40xc2x0 C., xcex2-ketoester (viii), which is a resulting product, may be decomposed to reduce the reaction yield.
The reaction time of the above-mentioned reaction is not particularly limited and the reaction completes generally in 15 min-30 min.
The solvent to be used for the above-mentioned step viii-2-1 and step viii-2-2 may be any as long as it does not inhibit the reaction and ethers such as THF, dioxane, dimethoxyethane and the like, or a mixed solvent of the ethers with any solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene and the like, aliphatic hydrocarbons such as heptane, hexane, octane and the like can be preferably used. In the case of a mixed solvent, they are mixed at a conventionally known general proportion to make the total amount fall within the above-mentioned range. The solvents to be used for the above-mentioned steps viii-2-1 and viii-2-2 may be the same or different.
The amount of the solvent to be used is generally 1000 mL-5000 mL relative to 1 mole of imidazolide (vii), which is preferably 2000 mL-3000 mL for the smooth progress of the reaction and enhanced productivity.
xcex2-Ketoester (viii) can be isolated and purified by a known isolation method (e.g., extraction, drying and the like) and by a known purification method (e.g., crystallization, silica gel column chromatography method and the like), or may be used as it is in a reaction mixture without isolation and purification.
The malonic acid monoester (v) to be used for the above-mentioned method can be obtained by conventionally known various methods, and commercially available ones can be used.
According to the above-mentioned method, xcex2-ketoester (viii) can be produced efficiently at a lower cost than conventional methods. That is, the above-mentioned method does not use expensive N,Nxe2x80x2-carbonyldiimidazole and 1 equivalent amount or 2 equivalent amounts of imidazole compound (iv) is sufficient for reaction, thereby affording production of xcex2-ketoester (viii) efficiently at a lower cost.
The production method of imidazolide (vii) for the above-mentioned method may be esterification, amidation and the like besides synthesis of xcex2-ketoester.
In the above-mentioned production method, by using (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid [(R)-carboxylic acid (III)] (i.e., a compound of the formula (vi) wherein R1d is 2-hydroxy-2-(2-phenylethyl)pentyl) as carboxylic acid (vi) and setting various same reaction conditions as those for this method, (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoic acid ester [(R)-carboxylic acid ester (X)] can be produced via imidazolide (IX).
The present invention is explained in detail by referring to Examples, which are not to be construed as limitative.
Note that xcex4 in NMR is expressed in ppm.
The optical purity was determined by the following method.
(Optical Purity)
A part of a sample (crystal, etc.) was suspended in toluene and aqueous caustic soda was added. The mixture was stirred for dissolution. The aqueous layer was obtained by partitioning, and made acidic with 10% hydrochloric acid and extracted with toluene. The toluene layer was concentrated and DMF, Hxc3xcnig""s base and benzyl bromide were added. The mixture was heated at 40xc2x0 C. for 30 min. To the reaction mixture obtained by the above-mentioned heating were added toluene and 10% hydrochloric acid and the aqueous layer was separated by partitioning. The toluene layer was concentrated. The residue was dissolved in isopropanol and both enantiomers [(R) isomer and (S) isomer] were separated by HPLC (solid phase: DAICEL CHIRALCEL OD, mobile phase: 4% isopropanol/hexane). The percentage of the peak area was measured, based on which the optical purity (% e.e.) was determined.